Preclinical good laboratory practice-compliant safety study to evaluate biodistribution and tumorigenicity of a cartilage advanced therapy medicinal product (ATMP).

BACKGROUND: The clinical development of advanced therapy medicinal products (ATMPs), a new class of drugs, requires initial safety studies that deviate from standard non-clinical safety protocols. The study provides a strategy to address the safety aspects of biodistribution and tumorigenicity of ATMPs under good laboratory practice (GLP) conditions avoiding cell product manipulation. Moreover, the strategy was applied on a human ATMP for cartilage repair. METHODS: The testing strategy addresses biodistribution and tumorigenicity using a multi-step analysis without any cell manipulation to exclude changes of test item characteristics. As a safeguard measurement for meeting regulatory expectations, the project design and goals were discussed continuously with the regulatory authority using a staggered scientific advice concept. Subsequently, the strategy was applied to co.don chondrosphere® (huChon spheroid), a tissue-engineered matrix-free ATMP of human normal chondrocytes. In both the biodistribution and tumorigenicity studies, huChon spheroids were implanted subcutaneously into 40 immunodeficient mice. Biodistribution was studied 1 month after implantation. A skin disc containing the huChon spheroid, two surrounding skin rings and selected organs were analyzed by validated, gender-specific, highly-sensitive triplex qPCR and by immunohistochemistry (IHC). RESULTS: No human DNA was detected in distant skin rings and analyzed organs. IHC revealed no direct or indirect indications of cell migration. Tumorigenicity was assessed 6 months after huChon spheroid implantation by palpation, macroscopic inspection, histology and IHC. No mice from the huChon spheroid group developed a tumor at the implantation site. In two mice, benign tumors were detected that were negative for HLA-ABC, suggesting that they were of spontaneous murine origin. CONCLUSIONS: In summary, the presented strategy using a multi-step analysis was confirmed to be suitable for safety studies of ATMPs.

Growth and Electrical Characterization of Hybrid Core/Shell InAs/CdSe Nanowires.

Core-only InAs nanowires (NWs) remain of continuing interest for application in modern optical and electrical devices. In this paper, we utilize the II-VI semiconductor CdSe as a shell for III-V InAs NWs to protect the electron transport channel in the InAs core from surface effects. This unique material configuration offers both a small lattice mismatch between InAs and CdSe and a pronounced electronic confinement in the core with type-I band alignment at the interface between both materials. Under optimized growth conditions, a smooth interface between the core and shell is obtained. Atom probe tomography (APT) measurements confirm substantial diffusion of In into the shell, forming a remote n-type doping of CdSe. Moreover, field-effect transistors (FETs) are fabricated, and the electron transport characteristics in these devices is investigated. Finally, band structure simulations are performed and confirm the presence of an electron transport channel in the InAs core that, at higher gate voltages, extends into the CdSe shell region. These results provide a promising basis toward the application of hybrid III-V/II-VI core/shell nanowires in modern electronics.

Corrigendum to "Evaluation of algorithmic, textual and pictorial forms of representation of standard operating procedures for error reduction in complex systems" [Heliyon 6 (2) (2020) e03291].

[This corrects the article DOI: 10.1016/j.heliyon.2020.e03291.].

Dataset of evidence based instruction forms for human error reduction in complex systems.

The article describes the export data of a flight research simulator experiment. The data show how different forms of presentation affect the behavior of instructions for test subjects. The representation forms algorithm, image and text are examined with regard to the number of top events, error frequencies, execution times and subjectively perceived workload. For this purpose, a study was carried out with n = 93 test persons in the research flight simulator, in which the test persons had the task of landing a passenger aircraft using the autopilot with different representation forms. 14 Possible work errors with 11 different representation forms. Further, there are questionnaire answers from test persons.

Evaluation of algorithmic, textual and pictorial forms of representation of standard operating procedures for error reduction in complex systems.

A new concept has been developed to compare different ways of presenting instructions for action for evaluation procedures. The representation forms algorithm (A), image (I) and text (T) are examined with regard to the number of top events, error frequencies, execution times and subjectively perceived workload. For this purpose, a study was carried out with n = 93 test persons in the research flight, in which the test persons had the task of landing a passenger aircraft using the autopilot with different representation forms. Possible work errors 14 with 11 different steps in the representation. Results of positive work-task landing plane: algorithm 58 % (1.7/14 errors σ = 1.5), text 62 % (1.5/14 errors σ = 1.1), image 93 % (0.8/14 errors σ = 1.1).